ABSTRACT: INTRODUCTION:In the United States, most antibiotics are prescribed in ambulatory settings. Human factors engineering, which explores interactions between people and the place where they work, has successfully improved quality of care. However, human factors engineering models have not been explored to frame what is known about ambulatory antibiotic stewardship (AS) interventions and barriers and facilitators to their implementation. METHODS:We conducted a systematic review and searched OVID MEDLINE, Embase, Scopus, Web of Science, and CINAHL to identify controlled interventions and qualitative studies of ambulatory AS and determine whether and how they incorporated principles from a human factors engineering model, the Systems Engineering Initiative for Patient Safety 2.0 model. This model describes how a work system (ambulatory clinic) contributes to a process (antibiotic prescribing) that leads to outcomes. The work system consists of 5 components, tools and technology, organization, person, tasks, and environment, within an external environment. RESULTS:Of 1,288 abstracts initially identified, 42 quantitative studies and 17 qualitative studies met inclusion criteria. Effective interventions focused on tools and technology (eg, clinical decision support and point-of-care testing), the person (eg, clinician education), organization (eg, audit and feedback and academic detailing), tasks (eg, delayed antibiotic prescribing), the environment (eg, commitment posters), and the external environment (media campaigns). Studies have not focused on clinic-wide approaches to AS. CONCLUSIONS:A human factors engineering approach suggests that investigating the role of the clinic's processes or physical layout or external pressures' role in antibiotic prescribing may be a promising way to improve ambulatory AS.